Despite recent insights into the molecular and cellular pathophysiology of the sickle cell syndromes, our understanding of the relationship of these subcellular events to the variable clinical expression of sickle cell disease remains largely speculative. We have sought to develop quantitative ways to clarify disease pathogenesis, as well as to assess severity and progression. Using calibrated phthalate ester separation method, which we previously described, we have now shown that there are at least three cellular processes contributing to the extensive red cell heterogeneity that is commonly observed in the sickle cell syndromes. Ocular studies of the patients show striking correlations between the extent of erythrocyte heterogeneity with conjunctival and retinal vessel pathology. As predictd by biophysical studies of polymer formation, we find that treatment of steady state sickle cell patients with selective arteriolar vasodilators results in a significant resolution of both acute conjunctival and retinal abnormalities, as well as an improvement in color vision performance. These salutary effects occurred in the absence of a direct drug-induced change in polymer formation, and suggests that inapporpriate vasospasm or frank vasoconstriction. perhaps in response to the altered rheology of red cell containing polymerized sickle hemoglobin is a significant contributing factor to the pathogenesis of sickle cell disease. This conclusion is also supported by our recent observation that "relative" hypertension is a significant risk factor for the occurrance of stroke in sickle cell patients. Using the technique of laser-Doppler velocimetry, we have found that forearom cutaneous microcirculatory flow undergoes a unique characteristic periodic pattern, which may become more "normalized" depending upon the fraction of non-S hemoglobins. We hope that these cellular and physiological measurements will allow us to understand better the extreme spectrum of disese manifestations.